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Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood

Oncogene volume 25, pages 1111–1117 (2006)Cite this article

Abstract

Supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of the CNS represent a biological and clinical enigma, despite advances in both molecular techniques and clinical management for these two rare embryonal brain tumors of childhood. Epigenetic changes hold great potential as possible disease mechanisms and may be manipulated therapeutically. We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT–PCR. In all, 17 samples of autopsy-derived normal appearing brain served as controls. Opposed to control tissues 19/24 sPNET and 4/6 AT/RT demonstrated aberrant methylation for the RASSF1A promoter region. Treatment of cell lines using 5-Aza-2′-deoxycytidine (5AZA) alone or in combination with trichostatin A (TSA) succeeded in re-establishing expression of RASSF1A in cell lines derived from a renal rhabdoid, an AT/RT and a medulloblastoma. A 5′ CpG-rich region of CASP8 was methylated in normal tissues and in tumors. However, CASP8 showed inconsistent expression patterns in normal and tumor tissues. Our results indicate that aberrant methylation of the RASSF1A promoter region may be of importance in the origin and progression of sPNET and AT/RT while the analysed 5′-CpG rich region of the CASP8 gene does not seem to play an important role in these tumors. Further studies of epigenetic changes in these rare tumors are warranted as their biology remains obscure and treatment efforts have been rather unsuccessfull.

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Acknowledgements

We appreciate B Kallinger's expert technical assistance and thank Professor W Paulus for neuropathological diagnosis. This study was supported by grants of the Deutsche Krebshilfe, the Wascowicz-, Cora Lobscheid- and the Karl Bröcker Stiftung.

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Germany

    J Mühlisch, A Schwering, H Jürgens & M C Frühwald

  2. University Children's Hospital of Zurich, Switzerland

    M Grotzer

  3. Department of Neurosurgery, University Hospitals of Wuerzburg, Germany

    G H Vince, C Hagemann & N Sörensen

  4. University Hospitals of Wuerzburg, Institute of Neuropathology, Germany

    W Roggendorf

  5. Institutes of Neuropathology and Pathology, University Hospital Münster, Germany

    C H Rickert

  6. Department of Medical Informatics and Biomathematics, University of Muenster, Germany

    N Osada

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  1. J Mühlisch
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  2. A Schwering
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  3. M Grotzer
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  10. H Jürgens
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Correspondence to M C Frühwald.

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Mühlisch, J., Schwering, A., Grotzer, M. et al. Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood. Oncogene 25, 1111–1117 (2006). https://doi.org/10.1038/sj.onc.1209137

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  • DOI: https://doi.org/10.1038/sj.onc.1209137

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